This invention is generally in the field of devices for the controlled transport of molecules across tissue barriers, such as for drug delivery or sampling of biological fluids.
Numerous drugs and therapeutic agents have been developed in the battle against disease and illness. A frequent limitation to the effective and efficient use of these drugs, however, is their delivery, that is, how to transport the drugs across biological barriers in the body (e.g., the skin, the oral mucosa, the blood-brain barrier), which normally do not transport drugs at rates that are therapeutically useful or optimal.
Drugs are commonly administered orally as pills or capsules. Many drugs, however, cannot be effectively delivered in this manner, due to degradation in the gastrointestinal tract and/or elimination by the liver. Moreover, some drugs cannot effectively diffuse across the intestinal mucosa. Patient compliance may also be a problem, for example, in therapies requiring that pills be taken at particular intervals over a prolonged time.
Another common technique for delivering drugs across a biological barrier is the use of a conventional needle, such as those used with standard syringes or catheters, to transport drugs across (through) the skin. While effective for this purpose, needles generally cause pain, local damage to the skin at the site of insertion, bleeding, which increases the risk of disease transmission, and a wound sufficiently large to be a site of infection. Needle techniques also generally require administration by one trained in its use, and are undesirable for long-term, controlled continuous drug delivery.
Similarly, current methods of withdrawal or sampling bodily fluids, such as for diagnostic purposes, using a conventional needle are invasive and suffer from the same disadvantages. For example, needles or lancets are not preferred for frequent routine use, such as sampling of a diabetic's blood glucose or delivery of insulin, due to the vascular damage caused by repeated punctures. No alternative methodologies are currently in use. Proposed alternatives to the needle require the use of lasers or heat to create a hole in the skin, which is inconvenient, expensive, or undesirable for repeated use.
An alternative delivery technique is the transdermal patch, which usually relies on diffusion of the drug across the skin. However, this method is not useful for many drugs, due to the poor permeability (i.e. effective barrier properties) of the skin. The rate of diffusion depends in part on the size and hydrophilicity of the drug molecules and the concentration gradient across the stratum corneum. Few drugs have the necessary physiochemical properties to be effectively delivered through the skin by passive diffusion. Iontophoresis, electroporation, ultrasound, and heat (so-called active systems) have been used in an attempt to improve the rate of delivery. While providing varying degrees of enhancement, these techniques are not suitable for all types of drugs, failing to provide the desired level of delivery. In some cases, they are also painful and inconvenient or impractical for continuous controlled drug delivery over a period of hours or days. Attempts have been made to design alternative devices for active transfer of drugs, or analyte to be measured, through the skin.
For example, U.S. Pat. No. 5,879,326 to Godshall et al. and PCT WO 96/37256 by Silicon Microdevices, Inc. disclose a transdermal drug delivery apparatus that includes a cutter portion having a plurality of microprotrusions, which have straight sidewalls, extending from a substrate that is in communication with a drug reservoir. In operation, the microprotrusions penetrate the skin until limited by a stop region of the substrate and then are moved parallel to the skin to create incisions. Channels in the substrate adjacent to the microprotrusions allow drug from the reservoir to flow to the skin near the area disrupted by the microprotrusions.
U.S. Pat. No. 5,250,023 to Lee et aL. discloses a transdermal drug delivery device, which includes a plurality of needles having a diameter in the range of 50 to 400 μm. The needles are supported in a water-swellable polymer substrate through which a drug solution permeates to contact the surface of the skin. An electric current is applied to the device to open the pathways created by the needles, following their withdrawal from the skin upon swelling of the polymer substrate.
PCT WO 93/17754 by Gross et al. discloses another transdermal drug delivery device that includes a housing having a liquid drug reservoir and a plurality of tubular elements for transporting liquid drug into the skin. The tubular elements may be in the form of hollow needles having inner diameters of less than 1 mm and an outer diameter of 1.0 mm.
While each of these devices has potential use, there remains a need for better drug delivery devices, which make smaller punctures or incisions, deliver drug with greater efficiency (greater drug delivery per quantity applied) and less variability of drug administration, and/or are easier to use. In view of these needs, microneedle devices have been developed, which are described in U.S. Ser. Nos. 09/095,221, filed Jun. 10, 1998, and 09/316,229, filed May 21, 1999, both by Prausnitz et al., and PCT WO 99/64580 and PCT WO 00/74763, which are hereby incorporated by reference. It would be advantageous, however, to provide additional methods of manufacturing devices having microneedles, particularly using materials and processes that are cost-effective and expand the range of useful properties and functions of the microneedles. It would also be useful to have biocompatible and biodegradable microneedles and increased ease of manufacture.
It is therefore an object of the present invention to provide an expanded selection of methods and materials for making and using microneedle devices for relatively painless, controlled and safe delivery or withdrawal of molecules across biological barriers such as skin.
It is a further object of the present invention to provide microneedle devices which can be produced inexpensively.
It is another object of the present invention to provide techniques for producing complex microneedle structures, yielding a variety of useful properties and functions of the microneedles.